COMPLETING THE CIRCUIT AT THE CENTER FOR BRAIN SCIENCE

by
Patricia Thomas

August 12th, 2004

Joshua R. Sanes, Director for Harvard's Center for Brain Science

In 1967, Harvard University Press published The Dance Language and Orientation of Bees, Karl von Frisch’s landmark account of the 20 years he spent deciphering the secret code of bees. He was the first to realize that a honeybee scout, upon returning to the hive, uses precisely choreographed dance moves to tell a rapt audience of foragers exactly which direction and how far they must fly to collect food for the colony. In 1973, this tour de force of observational biology earned the Austrian ethologist a Nobel Prize.

Since von Frisch collected his prize, scientists have sequenced the genome of honeybees, manipulated their genes, identified many of their proteins, and done a hundred other clever things in the lab. What they have failed to create is a coherent narrative of neural events that begins when the bee identifies a luscious flower and culminates in his dance, which remains as puzzling today as it was before von Frisch began his vigil at the hive.

And bees aren’t the only problem.

"In fact, no one has ever found an actual, physical circuit and proved that it underlies a specific behavior in any animal," says Joshua R. Sanes, who recently became the first director of Harvard’s new Center for Brain Science (CBS). Mapping such circuits is exactly the sort of mystery the new center aims to solve. "If we really knew what the physical basis for a behavior is, then we could tackle questions such as how behavior develops and why an infant’s behavior is so different from that of a grown-up," says Sanes. Armed with a better understanding of neural circuitry, scientists could discover much more about how healthy brains work, how circuitry alters with aging, and what goes awry in disease.

Long Time Coming

In 1999, neuroscience was one of three emerging scientific areas that then-Dean Jeremy Knowles identified as worthy of significant support from the university (the other two were genomics research and structural biology). About 30 faculty members, representing 5 Faculty of Arts and Sciences (FAS) departments and the Harvard Medical School’s Department of Neurobiology, served long hours on committees forging a mission statement and an administrative structure for what was initially called the Center for Systems Neuroscience. (The name was recently changed to avoid confusion among neurobiologists, for whom the term "systems neuroscience" connotes studies with nonhuman primates.)

A key player in the neuroscience effort was Markus Meister, Tarr Professor of Molecular and Cellular Biology, who not only talked about interdisciplinary approaches to brain science but also walked the walk. This physicist-turned-biologist had already teamed up with psychologists to investigate the visual system, and his lab biophysics and engineering students shared benches with biology concentrators.

Daniel S. Fisher, Professor of Physics, was among the faculty members attracted to the neuroscience initiative. "Of all the proposals, I thought neuroscience was the most forward-looking," he says, in part because it was animated by "intellectual kinds of questions, not just technology, and it had the potential for linking expertise from many different fields."

To jump-start the new center, FAS recruited Sanes as director and Jeff W. Lichtman as its first senior faculty member. The two were long-time collaborators at Washington University School of Medicine in St. Louis, and this summer they moved into adjacent labs in MCB’s Sherman Fairchild Biochemistry Building. (For more information about Sanes and Lichtman and their research, click here.)

Leveraging the Start-up

Hiring the right people is crucial for any new venture, and the center is no exception. FAS equipped Sanes with 5 full-time faculty equivalents, which he will allocate as half-time support for 10 recruits who will hold joint appointments at the center as well as in a department. Lindsley Professor of Psychology Stephen M. Kosslyn calls this plan "a major win" for his department and expects it to speed recruitment of experts in such fields as neuroimaging and transgenics. CBS will also underwrite laboratory start-up costs for new faculty and will be able to provide space once the Northwest Building is complete.

The emphasis will be on attracting researchers whose expertise advances the center’s core mission, which Sanes sees as having three major components:

Finding neural circuits that are simple enough to map at a physical level. This could mean using very simple models, such as the nematode C. elegans, or studying very accessible parts of a more complex animal’s nervous system. Here, Sanes says, the expertise of colleagues in the Department of Organismic and Evolutionary Biology will be essential.

Identifying behaviors that are simple enough to be understood, such as the honeybee’s dance or a highly specific behavior in a larger animal. Psychologists not only have many theoretical frameworks for studying behavior, Kosslyn says, but also "know how to train animals and design tasks that are very precisely targeted."

Building better microscopic tools for seeing the neurons researchers want to map, creating technologies for imaging and recording the activities of large ensembles of neurons, and developing computational and theoretical ways of interpreting the massive data sets these approaches generate. In an era when microarrays can measure what 30,000 different molecules are doing at once, "human intuition doesn’t work anymore," Sanes says. This is where FAS’s tremendous depth in fields including mathematics, physics, engineering, and computer science will be indispensable.

Survey a group of neuroscientists, and most will agree that "the next big questions are related to cognition and perception, very high-level faculties," says Catherine Dulac, Professor of Molecular and Cellular Biology, who uses mice to investigate the olfactory system. Although researchers at some institutions believe that only primate experiments can address big issues such as thought and memory, Harvard’s new center is set apart by Sanes’ conviction that "using genetically tractable animals might lead to a breakthrough in neuroscience," Dulac says. Kosslyn also endorses this approach, adding that spoken language may be the only neural function that can’t be addressed using animal models.

Brain Gain for Students

Since the early 1990s, Harvard students have been clamoring for more courses about the brain, the mind, and behavior. "Interest has outstripped the capacity of FAS undergraduate programs to provide course material," says Carla Shatz, chair of the Department of Neurobiology at Harvard Medical School. Some of her department’s professors currently teach undergraduates, and they plan to continue. But every new faculty member brought in by CBS "will make for a richer curriculum," Shatz says.

Although departments control their own faculty’s classroom assignments, Sanes expects the center to help coordinate neuroscience offerings across departments. Sanes and Lichtman have both taught introductory neuroscience, and although the details aren’t yet settled they hope to create a course that reaches a broad spectrum of undergraduates.

As new CBS faculty members set up their laboratories, research opportunities expand for students at all levels. "Because these labs will be part of a center, the training possibilities will be tremendous," says Dulac. "Instead of just learning to handle a single channel, for example, students will be able to talk to and learn from people working at many different levels of systems neuroscience."

Sanes’ laboratory is a case in point. In July, a troop of postdocs, grad students, and technicians unpacked truckloads of crates and packing boxes that had just arrived from St. Louis. In August, the first Harvard undergraduate reported for work in Sanes’ new lab.